Akkermansia as a target for obesity: authors comment

Using mice models, scientists from UCL and WUR found that Akkermansia muciniphila could have a role in reversing high-fat diet-induced metabolic disorders, in this study obesity and type-2 diabetes. The two first authors, Amandine Everard and Clara Belzer, having respectively a background in Pharmaceutical Sciences and Molecular Microbiology accepted to give us their feedback on their main findings.

1) What is the context of this study?

Our team investigates the cross-talk between gut microbiota and the host metabolism involved in obesity and type-2 diabetes. In this field, we have previously discovered that high-fat diet-induced obesity is characterized by gut microbiota alterations, gut barrier disruptions and inflammation. In a previous study, we demonstrated that gut microbiota modulations using prebiotics improved gut barrier functions, inflammation and glucose and lipid metabolism in obese mice. Interestingly, in these studies we had pointed out that Akkermansia muciniphila was the bacterium the most affected (increased) by the prebiotic treatment, calorie restriction and weight loss in both humans and mice. Moreover, the abundance of Akkermansia muciniphila correlated with all the beneficial effects of prebiotic treatment.

However these correlations did not prove the beneficial effects of Akkermansia muciniphila in obesity and type-2 diabetes. Therefore, to investigate the direct implication of Akkermansia muciniphila on obesity and type-2 diabetes we administered the bacteria to high-fat diet-induced obese mice.

2) What was the most challenging part of this study?

The most difficult part of this study was to challenge the proof of concept that one specific bacterium could be pertinent when studying pathologies such as obesity and related disorders affecting a huge part of world population. Indeed, the major weaknesses when investigating the role of gut microbes in the etiology of obesity and type-2 diabetes is the reliance on conclusions that are based on correlative data between bacteria and physiological parameters. This is due to the fact that most of the gut bacteria have been identified at the phylogenetic level (i.e., through metagenomic approaches) but have never been cultured.

3) What were the main findings?

i. Obesity is associated with a decrease in the abundance of Akkermansia muciniphila in gut microbiota.

ii. Akkermansia muciniphila is able to cross-talk with the intestinal epithelium to control gut barrier functions in the pathophysiology of obesity. We show for the first time that obesity is associated with a decrease in the mucus layer thickness recovering epithelial cells. Interestingly, Akkermansia muciniphila is the dominant human bacterium that abundantly colonizes this nutrient-rich environment. We found that living Akkermansia muciniphila was able to control mucus layer production by the host and restore mucus layer thickness in high-fat diet-induced obese mice thereby reducing gut permeability.

Although we have discovered several putative targets (e.g., the endocannabinoid system, Reg3 gamma), more studies are needed to unravel metabolites and molecular targets involved in the cross-talk between Akkermansia muciniphila and epithelial host cells to control obesity.

5) How could your study help clinicians in the future?

These results provide a rationale for the development of a treatment using Akkermansia muciniphila for the prevention or treatment of obesity and its associated metabolic disorders. Moreover, this study also reveals novel mechanisms of interaction between gut microbiota and intestinal host cells. These mechanisms could constitute new interesting pharmacological targets for obesity and type-2 diabetes.

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Gut Microbiota for Health has been created by the Gut Microbiota and Health Section of the European Society for Neurogastroenterology & Motility (ESNM), member of United European Gastroenterology (UEG)